This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall objective of this study is to evaluate the toxicity and efficacy of two microbicides [unreadable]an HIV entry inhibitor (RC-101) and an HIV non-nucleoside reverse transcriptase inhibitor (CSIC) against RT-SHIV virus challenge. There are five specific aims to achieve this objective. Aim 1 will assess the vaginal and systemic toxicity of RC-101 and CSIC. Microbicide rings will be placed in the vaginal vault of Rhesus macaques (Macaca mulatta). Blood, tissue sampling and colposcopies will be performed to determine vaginal and systemic absorption and toxicity as well as to determine the release rate of the microbicides. Aim 2 will determine the minimal infectious dose of RT-SHIV by the vaginal route. Six Rhesus macaques will be inoculated with RT-SHIV via the vaginal route and blood samples will be collected to monitor viral infection. To date, two animals have been treated with Depo-Provera and inoculated with 10 TICD50 RT-SHIV. The remaining four animals will be inoculated with the dose dependent upon the results of the first two animals. Aims 3, 4 and 5 will determine the efficacy of each microbicide individually, as well as in combination, against RT-SHIV challenge. Vaginal rings containing either RC-101, CSIC, a combination of the two or the vehicle only (6 animals in each group) will be implanted vaginally. The animals will be challenged vaginally 24 hours later with RT-SHIV. Blood samples, vaginal biopsies and endoscopic intestinal pinch biopsies will be collected to monitor for viral infection. Thus far, six animals have been assigned to test the toxicity and efficacy of CSIC (Aims 1 and 3).